Understanding machine learning applications in dementia research and clinical practice: a review for biomedical scientists and clinicians

Several (inter)national longitudinal dementia observational datasets encompassing demographic information, neuroimaging, biomarkers, neuropsychological evaluations, and muti-omics data, have ushered in a new era of potential for integrating machine learning (ML) into dementia research and clinical practice. ML, with its proficiency in handling multi-modal and high-dimensional data, has emerged as an innovative technique to facilitate early diagnosis, differential diagnosis, and to predict onset and progression of mild cognitive impairment and dementia. In this review, we evaluate current and potential applications of ML, including its history in dementia research, how it compares to traditional statistics, the types of datasets it uses and the general workflow. Moreover, we identify the technical barriers and challenges of ML implementations in clinical practice. Overall, this review provides a comprehensive understanding of ML with non-technical explanations for broader accessibility to biomedical scientists and clinicians. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-024-01540-6.


Introduction
Alzheimer's disease (AD), the major cause of dementia, is a progressive neurodegenerative disorder that predominantly affects older people [1].The accumulation of amyloid-beta (Aβ) and formation of neurofibrillary tangles marked by tau phosphorylation in the brain are the key hallmarks of AD [1].Clinically, the disease can be divided into three stages: 1) preclinical AD i.e., cognitive unimpaired (CU) people with amyloid accumulation in the brain, 2) prodromal or mild cognitive impairment (MCI) and 3) Alzheimer's dementia (ADem) [1].This disease trajectory can vary between individuals, and preclinical AD can occur 15-20 years prior to ADem [1].
Observational longitudinal dementia datasets have been collected in diverse age groups across several (inter) national dementia cohorts (Table 1), providing rich information that enhances the granularity and scope of data science research.These datasets encompass a broad spectrum of information including biomarkers, genetics, neuropsychological evaluations, neuroimaging, omics, etc. (Table 2).Traditional statistical methods, constrained by  Speech and language [38] Microphones & recording -None Acoustic, prosodic, etc -rigid assumptions and a limited ability to handle complex interactions have shown limitations in processing these multi-modal datasets, prompting an exploration of more adaptive and comprehensive techniques such as machine learning (ML) [2].ML is a class of algorithms that enable computers to analyze data and make decisions by identifying patterns specific to tasks [3].These techniques can detect subtle patterns and trends in large datasets, significantly enhancing the effectiveness and productivity of data-driven research.In addition, ML has already proven successful in tracking disease, including market-ready products (e.g., Vivid E80 [4]) and FDA-approved devices (e.g., Apple's Atrial Fibrillation History Feature [5]).
The development of anti-Aβ monoclonal antibodies, such as donanemab [40] and lecanemab [41], has shown promising results in reducing cognitive decline in early treatment scenarios.This underscores the importance of timely intervention.ML can enhance early detection accuracy and personalized stimulation by determining the most effective timepoint to adminster antibodies in the right patients, thereby maximizing their therapeutic benefits.However, it must be noted that while ML can aid in identifying individuals likely to benefit, our global health systems are not fully equipped to provide these early interventions.Monoclonal antibodies require costly monitoring for brain bleeds, which presents challenges not only in funding the necessary scans but also in accessing scanners within a reasonable distance for patients.A recent study showed that novel biomarkers including microRNAs, metabolites and proteins have been identified using ML approaches [42].Furthermore, it has been demonstrated that patient-level simulations by ML can predict disease trajectories [43], estimate the likelihood of transitioning from MCI to ADem [44] or even successfully forecast the time-to-event outcomes survival probability for MCI participants [45].
Here we provide a comprehensive overview of ML application in dementia (ML-dementia) using non-technical terms to enhance accessibility to a broad readership.Specifically, we evaluate ML from a historical perspective and discuss typical workflows, successful applications within 5 years and challenges-highlighting the evolving utility of ML in biomedical research to enhance diagnosis and management of dementia.

Types of ML
ML includes a variety of algorithms designed to learn from data to meet a predefined goal, such as identifying patterns or making predictions about future states.The model updates its settings or '(hyper-)parameters' based on feedback from performance metrics known as 'loss functions' , which assesses the accuracy of the model's predictions compared to actual outcomes.Once the model is optimally trained, it can use real-world data to achieve the predefined task [46].ML techniques are primarily divided into three categories: unsupervised learning, supervised learning, and reinforcement learning, with the first two being more commonly used in dementia research.These categories are discussed in detail below and their advantages and limitations are summarized in Table 3.

Supervised learning
Supervised learning explores the relationship between input features and the corresponding target outputs, also known as labels.In dementia research, supervised learning can be further categorized based on the predictive target, for instance, classification tasks dealing with categorical labels (e.g., ADem vs CU), regression tasks handling numerical labels (e.g., Clinical Dementia Rating-Sum of Boxes [CDR-SB] and Mini-Mental State Examination [MMSE]).Once the model is trained, it can then make predictions on unlabelled data of the same input.

Unsupervised learning
Unsupervised learning operates on unlabelled data, which focuses on uncovering patterns or relationships without considering any predefined labels.This approach includes 1) clustering tasks such as identifying subtypes of dementia based on biological, neuropsychological, and demographic features and 2) data compression such as using principal component analysis to simplify and summarize complex data.

Reinforcement learning
Reinforcement learning (RL) is used to learn and improve decision making by continuously receiving feedback through interaction with external conditions and observing the response.This approach is less commonly used than the supervised and unsupervised methods.RL can be classified as model-free and model-based types; model-free RL operates without a predefined model, while model-based RL is preferred for incorporating domain knowledge (i.e., existing clinical knowledge).RL could mainly be employed to simulate and predict cognitive states, as well as to estimate the probability of transitioning between cognitive states.

Statistical analysis versus ML approaches
Traditional statistical methods include a hypothesisdriven approach and statical inference (i.e., generalizing findings from a subset of data to a large population).Such approach relies on strong assumptions about the data, e.g., the data follows a normal distribution to fit existing theoretical models [50].However, these traditional statistical methods often encounter practical challenges in complex real-world scenarios, as the assumptions made may not be satisfied in clinical practice [2].In contrast, ML adopts a more data-driven approach with minimal assumptions, and it concentrates on prediction rather than inference [2].However, statistical models and ML techniques sometimes overlap; e.g., both methods often employ linear and logistic regression models to meet statistical goals or to achieve simple linear predictions in ML contexts.It must be noted that ML possesses the capability to process and analyze extensive and complex datasets, such as omics data, effectively uncovering patterns or capturing interactions that might be omitted or overlooked by the traditional statistical analysis [2].Therefore, ML is often beneficial to clinical research, where data is inherently multidimensional with a diverse array of variables.

The history and typical workflow of ML techniques in dementia research and clinical applications
Prior to the year 2000, research primarily focused on clarifying the genetic and biochemical foundations of AD, with significant emphasis on the roles of Aβ and familial genetic mutations [51].In the subsequent decade (2000-2010), scholarly attention shifted towards differentiating AD from CU mostly using ML model such as support vector machines alongside brain imaging techniques [52].In the following five years or so, researchers focused on predicting clinical progress in MCI patients using multi-kernel support vector machine (SVM, a ML model) with longitudinal data from magnetic resonance imaging (MRI) and positron emission tomography (PET) [53].Since then, ML or deep learning, a subset of ML that uses neural network to simulate the learning process of human [54], has been used to classify disease subtypes and stages.Similar to how the human brain employs interconnected neurons for information processing, neural networks in ML use nodes (artificial neurons) and their interconnections to mimic the brain's structure and functionality.This design facilitates pattern recognition and decision-making.For instance, Ramzan et al. [55] utilizes resting-state function MRI with Residual Network architecture to classify AD into: CU, significant memory concern, early-MCI, MCI, late-MCI, and ADem.In more recent years, the adoption of advanced deep learning architectures, such as time-series models has expanded.For example, hybrid deep learning frameworks based on Bidirectional Long Short-Term Memory models leverage multimodal data (i.e., MRI, PET, and neuropsychological evaluation) to enhance the classification of CU and early MCI [56].A timeline summarizing the use of ML in dementia research is presented in Fig. 1.
The general workflow to build and apply the MLdementia model is summarized in Fig. 2, which can be separated into six key steps, including 1) Intended application, 2) Data selection, 3) Data pre-processing, 4) Model Construction, 5) Model evaluation, and 6) Maintenance.We have provided a detailed description for each step in Supplementary Material -ML workflow.

Data used in ML-dementia studies
Several observational dementia datasets have been used for ML model construction and validation (Table 1), such as the Australian Imaging, Biomarker and Lifestyle (AIBL) study [57] and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study [13].These datasets are often longitudinal, involving thousands of participants, spanning several decades with regular follow-ups, and some are still actively recruiting.These datasets feature a diverse range of participant demographics, typically focusing on middle-aged adults from various racial, ethnic and educational backgrounds.Each dataset has a distinct focus.For instance, Open Access Series of Imaging Studies [OASIS] [16] concentrate on brain imaging, while the Religious Orders Study and Rush Memory and Aging Project [ROSMAP] [9] aim to understand aging processes.Data collection and testing within the same dataset can vary depending on the project's phases or aims.For example, ADNI adapts its data collection strategies across five phases, and OASIS divides its datasets to address specific research goals.While most datasets listed in Table 1 primarily address AD, others such as the UK Biobank [15] and the Framingham Heart Study [6], provide a broader insight across various health outcomes within larger cohorts.
A variety of data/sample collection methods have been employed in these studies, which can be categorized as per their level of invasiveness (Table 2).Invasive methods, such as cerebrospinal fluid collection through lumbar puncture, are commonly used to obtain biomarkers (Aβ and tau) and markers of neurodegeneration [1].The AT(N) 2018 framework [58], categorizes the progression of AD into different stages based on specific combinations of these biomarkers (Table 4).Compared to lumbar puncture, venous blood collection is considered less-invasive, and often used for biomarker research and omics (genomics, transcriptomics, proteomics, and metabolomics) analysis [59].Non-invasive methods such as MRI and PET are employed to study brain structure and Aβ levels [1].Neuropsychological evaluation (Table 5) are also noninvasive, which are quantitative measures of cognitive functions across various disease stages (Table 6) [60].Demographic information, lifestyle data and medical history are often self-reported or collected using questionnaires and are used as baseline predictors in the majority of studies [61].

Existing ML-dementia models using non/ less-invasive data
The following section reviews ML models using input data collected via non-/moderately invasive approaches.These data include demographics (age, gender, ethnicity, family history), medical history, neuropsychological    7 and Fig. 3.

Dementia subtyping
AD is the major cause of dementia, followed by vascular dementia, frontotemporal dementia, and dementia with Lewy bodies [90].Accurate differential diagnosis is important for clinicians to offer the most suitable care options to the patients [91].Recent studies utilizing ML and deep learning models have shown relative high accuracy in differential diagnoses by incorporating metabolomics [67] and neuroimaging [64][65][66] (Table 7A).For instance, Qiang et al. [67] established the associations between 249 metabolites and type of dementia (allcause dementia, ADem, and vascular dementia) using UK Biobank data.The study employed Cox proportional hazard models and light gradient boosting machine algorithms to generate a metabolic risk score.This score when combined with demographic and neuropsychological test scores achieved an AUC of 0.85 (AUC approaching 1 indicates excellence in discrimination) for the classification of different types of dementia.By employing neuroimaging data, Castellazzi et al. [92] used the adaptive neuro-fuzzy inference systems to distinguish between ADem and vascular dementia.This achieved over 84% accuracy using a combination of features from resting-state functional MRI and diffusion tensor imaging.Moreover, another independent research group [65] achieved ~ 80% accuracy in differentiating dementia with Lewy bodies from ADem using structural MRI data and a residual neural network.Finally, Nguyen et al. [66] introduced an innovative approach, by integrating 3D U-Nets with a multi-layer perceptron classifier to discern ADem from frontotemporal dementia through structural MRI images, attaining an AUC of 0.94.Although these studies achieved high diagnostic accuracies (~ 80%), only Nguyen et al. [66] validated their model using an external dataset.This raises concerns about the generalizability of these findings and suggests that potential cohort bias cannot be ruled out.It is crucial to further validate these models prior to clinical trial and implementation.Moreover, these studies appear to focus on the differential diagnosis between vascular dementia and ADem (Qiang et al. [67] and Catellazzi et al. [92]) and between frontotemporal dementia and ADem (Nguyen et al. [66]).Future research could explore the possibility of differentiating multiple subtypes of dementia using a single model.Furthermore, all these studies, except Qiang et al. [67], leveraged advanced imaging techniques to capture intricate details of the brain.The reliance on high-resolution imaging data necessitates substantial resources, making it challenging to implement the new technology in clinics.

Disease staging
Predicting disease stages using either a binary classification (CU vs ADem, CU vs MCI + ADem, CU vs MCI, MCI vs ADem) or CU/MCI/ADem classification is commonly used in ML-dementia.These typically employ omics data [69,74], neuropsychological evaluation [70], and neuroimaging [68,70,71] (Table 7B).Mahendran et al. [74] demonstrated that deep belief network-based approach (accuracy 82%) outperformed SVM (accuracy 78%) and Naïve Bayes (accuracy 76%) in binary classification of CU and ADem using their multi-omics data.In another study, Wang et al. [69] utilized six differentially expressed metabolites, three metabolic pathways and a random forest model to differentiate the MCI + ADem group from CU, and they achieved an AUC of 0.77.MRI data have also been employed to facilitate disease classification.For instance, Naz et al. utilized only structural MRI data [71], and achieved a classification accuracy of 99.27, 98.89 and 97.06% for MCI/ADem, ADem/CU, and MCI/CU, respectively.To generate more complex models, multimodal data (e.g., demographic, medical history, brain volume, neuropsychological evaluation and genetics) have been integrated, such as convolutional neural network model for disease stage classification.For example, using multimodality, Venugopalan et al. [70] achieved a classification accuracy of 83% for CU, 74% for MCI and 85% for ADem.
We noted that model development in most of these studies were challenged by an imbalanced dataset, with AD and MCI often being underrepresented compared to CU individuals due to disease prevalence.Interestingly, Naz et al. [71] manually balanced the dataset by eliminating some of the CU participant data (CU = 95, MCI = 146, ADem = 95).However, this approach reduces the overall dataset size, possibly leading to the model not capturing all critical features for accurate classification [93].Model overfitting is also expected from using such a small dataset [94].Future studies could focus on enriching AD and MCI participant data; however, this is currently less practical due to a lack of harmonized datasets that allows data pooling.An alternative approach is to intentionally recruit MCI and ADem participants, as done by Kwak et al. [77]; however, these data may be less suitable for studying the onset and progression of AD.Another major issue is that the classification accuracy is usually less satisfactory for differentiating MCI from AD, as has been reported by Wang et al. [69] and Naz et al. [71].Using multimodal data could be a potential solution [70], nonetheless, future studies are required to confirm whether their observations are dataset dependent.

Disease progression/trajectory prediction
The prediction of future disease states or neuropsychological outcomes can be achieved using classification and regression models, as well as simulating disease trajectories using more complex deep learning models (Table 7C).Most classification models categorize MCI-to-dementia progressors and non-progressors.For example, Rye et.al.[72] achieved a 75% of accuracy in predicting whether MCI participants progress to dementia using a random forest model, where neuropsychological evaluation, hippocampal volume and Apolipoprotein E (APOE) genotype were used as input features.An ensemble model was employed by Mofrad et al. [79] for such prediction, where MRI and neuropsychological evaluation were used to achieve a 77% accuracy.Regression models often employ neuropsychological evaluation, such as CDR-SB, ADAS-Cog, and MMSE [77,78,82], to estimate disease severity over time.For example, Lian et al. [78] employed a multitask weakly-supervised Attention Network, which is a regression model that built on structural MRI data collected from CU, MCI progressor, MCI non-progressor, and ADem participants to predict 3-year future CDR-SB, ADAS-Cog, and MMSE scores.This model has achieved promising results, with a root-mean-squared error of 1.5, 5.7, and 2.2 for each score, respectively.For disease trajectory simulation, Bucholc et al. [82] has combined unsupervised and supervised learning techniques, where participants were categorized by their cognitive score trajectories (stable vs deterioration over 2-3 years).The trajectories of each category were then analyzed using random forest, support vector machine, and linear regression (supervised).This approach achieved a ~ 90% accuracy in predicting seven different neuropsychological test scores over 1-year and 2-year intervals, from the correspondent baseline scores.A more complex model, Long Short-Term Memory Recurrent Neural Networks, was used by Mukherji et al. [81] to simulate the trajectory for five neuropsychological tests.This model achieved a prediction accuracy of 85 and 83% for 2-year and 4-year, respectively.Recent work has also focused on dynamically predicting the risk of dementia onset.This is typically achieved using a Cox model, combined with functional data analysis to model longitudinal neuropsychological outcomes.For example, Jiang et al. [76] utilized the functional ensemble random survival forest to characterize the joint effects of neuropsychological evaluation in predicting disease progression, Fig. 3 Types of data used in ML models.A Counts of various data types used in four major ML-dementia applications; B Donut chart showing the distribution of data types used in the selected studies (Table 7); C Venn diagram illustrating the overlap of data types used in the selected studies shown in Table 7.This figure is created using Canva (www.canva.com) specifically to predict the time to AD conversion in individuals with MCI and to provide personalized dynamic predictions.This approach achieved an AUC of approximately 0.90 over an average follow-up period of 31 months.Similarly, Zou et al. [83] proposed a multivariate functional mixed model framework to simultaneously model multiple longitudinal neuropsychological outcomes and the time to dementia onset, achieving an integrated AUC of over 0.80, with the mean time to visit being 1.12 years.
Mukherji et al. [81], Bucholc et al. [82] and Lian et al. [78] predict disease progression over a fixed interval, while Jiang et al. [76] and Zou et al. [83] simulate disease progression.It should be noted that simulation methods introduce higher variance and complexity compared to fixed interval models [95]; however, they can predict disease status at any time point, whereas fixed interval models can only predict disease status at the end of the interval.Different models may suit varying clinical needs or patient expectations, each balancing its own advantages and limitations.In addition, these complex models are prone to overfitting [94], capturing noise that does not generalize to unseen data.This issue could be exacerbated in studies where the training datasets are relatively small, such as that for Jiang et al. [76] (165 MCI stable, 137 MCI progressor).We have also noted that most of these models, except Lian et al. [78], involve various neuropsychological tests, which often differ between studies.This makes it challenging for external validation and comparison between different models.Future studies should consider developing models based on neuropsychological tests that are routinely used in clinics for easier evaluation, validation and potential implementation.

Predicting Aβ and tau levels in the brain
ML models have shown promise in predicting AD biomarkers with reasonable accuracy (Table 7D).For predicting Aβ and p-tau levels in the brain, the problem is often simplified into a binary classification, e.g., normal vs high or negative vs positive.Langford et al. [85] employed the extreme gradient boosting algorithm, a scalable tree boosting model to predict Aβ PET positivity (standardized uptake values ≥ 1.15) from demographics (age, education, gender and family history), four neuropsychological tests and APOE genotype.,An AUC of 0.74 was achieved.Palmqvist et al. [84] used plasma Aβ 42 / Aβ 40 ratios, APOE genotype, and neuropsychological tests for a logistic regression with a lasso penalty model, and achieved an AUC of 0.83.In contrast, Lew et.al. [88] employed a logistic regression model for binary prediction of PET results (high versus low Aβ or p-tau) using MRI and other data (e.g., demographic, APOE genotype, neuropsychological tests and hippocampal volumes etc.).This resulted in an AUC of 0.79 for Aβ and 0.73 for p-tau.Using a seven-layer neural network, 3,635 plasma proteins, age and APOE genotype for the same prediction, Zhang et al. [89] achieved a lower AUC score for Aβ (AUC = 0.78) and p-tau (AUC = 0.67).Their performance is relatively lower than the other studies, which could possibly be due to high feature-to-sample ratio (3000 proteins in 800 participants), which can complicate model training and validation.
Notably, a universally accepted threshold to determine binary classification is lacking.For example, Langford et al. [85] used a threshold of 1.15, while Palmqvist et al.
[84] adopted a threshold of 0.738.Whether this would have impacted the prediction performance of the model is unclear.Future studies should consider standardizing this threshold to enable comparisons between models.Another issue with these studies is that the datasets used for model training are relatively small (e.g., 300 participants for Palmqvist et al. [84] and 800 participants for Zhang et al. [89]), possibly due to cost constraints associated with PET and MRI.Research funding bodies could play a role in encouraging (inter)national collaboration and data sharing, as well as endorsing standard data formats (especially for those high-cost experiments) to increase the size of datasets for more robust results.

Challenges and future directions
ML has been applied to clinical data analysis for more than two decades, and its widespread adoption in clinical research and healthcare has noticeably accelerated.This section will discuss the technical barriers, and the anticipated challenges and potential solutions to applying ML in clinical practice for dementia (summarized in Table 8).

Clinical data quality
Given the complex set up of longitudinal studies and heterogenous disease pathology, missing values, outliers, data imbalance are inevitable.Missing data is often due to incomplete responses, data collection errors, technical issues and participant withdrawal [96].Data scientists either disregard participants with missing data or use imputation techniques (e.g., mean imputation, multiple imputation by chained equations, etc. [97]).Outliers normally result from errors from record, measurement or misclassification.Statistic techniques, such as z-scores and interquartile range or box plot are used to detect outliers.Once identified, common approaches involve removing outliers, adjusting into specific percentile, or applying transformations to reduce the skewness of the data distribution [98].Data imbalance is a commonly encountered issue for dementia dataset, as MCI and ADem occur in a smaller population compared to CU.When MCI/ADem cases are significantly underrepresented compared to CU, it can lead to a biased model performance, where ML models trained on imbalanced data may prioritize the majority and struggle to accurately predict the minority [99].To address this issue, resampling techniques such as Synthetic Minority Over-sampling Technique [100] can be employed.
The quality of clinical data used to train ML models directly impacts the soundness of the model.The diagnoses are performed by clinicians and neuropsychologists [101,102], which can sometimes introduce human errors into the dataset.This is because diagnosis is complicated by that 1) preclinical AD is difficult to detect [103], 2) MCI can be misclassified [104], and 3) vascular dementia, Lewy body dementia, and frontotemporal dementia are sometimes misdiagnosed as ADem [105].Moreover, some neuropsychological tests are influenced by practice effects [106] (repeated testing can artificially improve performance over time), and education background [107] (poor performance for individuals who are less educated), potentially skewing results.Furthermore, the trajectory of dementia varies significantly among individuals due to the complex interplays of age, genetics, sex, and other comorbidities [108].Some individuals may experience a gradual decline in cognition over many years, while others show rapid deterioration.Many longitudinal studies employ an "up-to-interval" method [75], classifying participants into CU, MCI, ADem, and non-ADem within a specified follow-up period.However, this approach often falls short in capturing the disease trajectory of individuals experiencing gradual cognitive decline.In addition, older participants are more likely to withdraw from the study due to their dependency on others (e.g., reduced mobility discourage their participation), leading to their disease trajectory not fully captured.Cohort study designs can be enhanced to improve data quality.Longitudinal study designs should consider incorporating more objective diagnostic criteria, such as expanding the use of Aβ PET scans, and integration of blood-based biomarkers, tau, and neuroinflammation markers, to enhance the assessments accuracy.Additionally, developing strategies to prolong study follow-up duration is crucial for capturing the full progression of disease states over time.Research funding bodies could play a crucial role in driving this progress by prioritizing investment and providing support to longitudinal studies.

Data standardization
The existing longitudinal datasets exhibit a lack of uniformity and standardized approach in sample/data collection and record format, making it difficult to validate and compare metrics like accuracy, sensitivity, and specificity between ML models that built on different datasets [109].For example, although AIBL and ROSMAP collected depression related data, yet different scales were used-AIBL adapted the Hospital Anxiety and Depression Scale while ROSMAP used the Center for Epidemiological Studies Depression scale.The lack of uniformity in data collection could also be attributed to the intrinsic nature of the technology.For example, various platforms, techniques, and environmental factors could introduce biases and variabilities into omics dataset [110].In addition, omics data is often noisy and sparse, especially when detecting molecules of low abundance, and therefore more prone to batch effect.Furthermore, different annotation systems or reference databases used to identify proteins, metabolites, and genes can lead to mismatches and inconsistencies.Also, different omics dataset may lack of common features due to experiment set up.All these make it less practical to standardize the omics data.
To enhance the performance of ML models in dementia research, addressing variability in data collection methods is crucial.The Alzheimer's Dementia Onset and Progression in International Cohorts initiative [111] exemplifies the successful application of data harmonization, integrating data from five international dementia cohort studies, including the Adult Children Study, ADNI, AIBL, the Dominantly Inherited Alzheimer Network, and the National Alzheimer's Coordinating Center.Similar initiatives should be encouraged, as they are crucial for enhancing statistical power, and enabling more robust ML applications in dementia, leveraging the existing longitudinal datasets.In addition, publication of sample collection protocols, along with raising awareness of the requirements and benefits of data pooling for ML among biomedical and clinician scientists, could promote consistent data collection practices and enhance collaborative research efforts globally.Of paramount importance, inconsistencies in data formats can undermine the effectiveness of ML models.Advanced tools like 'dtool' provide practical solutions for standardizing data formats and enhancing quality by encapsulating data and metadata into consistent, unified dataset structures with readily accessible metadata for both the collective dataset and its individual files [112].Data repositories could endorse guidelines that only accept datasets meeting standardized criteria.

Data generalizability
A longitudinal dataset may lack of generalizability.The study setting and enrolment criteria would exclude certain populations based on ethnicity, education level, socio-economic status, or comorbid conditions.For example, research studies might exclude participants with severe cardiovascular diseases or advanced diabetes, arguing that these conditions could confound the cognitive assessments used to diagnose and track ADem progression [113].Moreover, studies that require participants to be English-speaking exclude individuals from a culturally and linguistically diverse background (e.g., the indigenous population in Australia, who have a higher risk of ADem).These exclusions can result in datasets that fail to fully represent the diverse population affected by dementia.The clinical application of ML models built from biased data will consequently be limited.Collaborative efforts between researchers, clinicians, and regulatory bodies are crucial in developing criteria that balance scientific rigor with practical feasibility.Furthermore, the major dementia longitudinal studies are often restricted to national boundaries, constraining their generalizability and the assessment of their performance in more border real-world scenarios.Researchers are encouraged to employ multiple datasets, where the model is trained on one dataset (e.g., ADNI) and validated on another dataset (e.g., AIBL) [114] to address this challenge.

Computational and memory burden
Computational and memory burden is another technical challenge to ML-dementia, particularly as recent studies focus on high-dimensional longitudinal omics data.Advanced tools such as the versatile toolbox MEFISTO [115] and the PALMO platform [116] are now capable of modelling spatial and temporal omics data.These tools utilize high-performance computing resources and implement various optimization strategies to improve processing efficiency.However, the high computational and memory demands of these algorithms can limit their applicability in AD studies that involve large sample sizes.Furthermore, the high volume of data requires a robust data management solution.Distributed computing platforms, like Apache Hadoop [117], can be employed to efficiently handle, store, and share the large-scale data, facilitating collaborative efforts across different research groups and locations.However, these platforms are not always affordable, creating a technical barrier.

From bench to clinic
Artificial intelligence (AI), such as ML, has already demonstrated success in disease tracking, as evidenced by FDA-approved devices like Apple's Atrial Fibrillation History Feature [5].While ML applications have yet to be implemented in dementia clinical practice, anticipated challenges must be considered for future implementation in dementia diagnosis and care.

Acceptance of ML tools by patients
The targeted population for ML-dementia tools is older adults, which raises questions about their readiness to accept these technological innovations [118].Many older adults are not as technologically adept as younger generations, making it challenging for them to understand ML and its potential in diagnosing and managing diseases.This lack of understanding can result in low trust in ML-generated results, leading to hesitation in their use for healthcare purposes.Moreover, some ML tools collect data using wearable devices, raising privacy concerns among older adults who may be unsure how their data will be used.Furthermore, not all older adults want to receive predictions about their disease progression or early detection due to psychological fears and anxieties [119].
To address these challenges and improve acceptance among older adults, several steps should be taken.Increasing public awareness of ML and its benefits in healthcare is crucial, as many people may not realize that AI/ML are already being used.Ensuring transparency in data usage and robust data security measures can help build trust, while offering a personalized approach where individuals can opt in or out of predictive analyses can promote autonomy [120].Providing comprehensive psychological support can help individuals cope with the emotional impact of potential diagnoses and empower them to make informed decisions about their health and care plans.By addressing these concerns through patient education, demonstrating the reliability and benefits of ML tools, and ensuring robust data security measures, we can foster greater acceptance of ML-dementia tools among older adults.

Acceptance of ML tools by clinicians
Clinicians tend to prefer techniques that are transparent and interpretable, aligning with conventional clinical reasoning.One of the barriers for clinicians to trust and uptake the output of ML models is the opaque nature of these algorithms, often referred to as "black boxes."ML models can obscure the logic behind their complex decision-making processes, sometimes producing results that cannot be easily justified by existing biomedical knowledge.The "black box" nature of ML potentially erodes clinicians' trust, hindering the adoption of these models in clinical practice.In response to these challenges, there is an increasing focus on developing explainable AI techniques, such as Local Interpretable Model-agnostic Explanations (LIME) and SHapley Additive exPlanations (SHAP) [121].These methods aim to make the decision-making processes of ML models more transparent and understandable, thereby can potentially enhance trust among clinicians.Another significant challenge is that many clinicians have not received formal training in ML, which can hinder their ability to effectively use and explain these tools to patients [122].Providing basic education about ML to clinicians and incorporating an AI/ML training component in medical school curriculum can enhance their ability to use innovative tools and communicate the benefits to patients.Of paramount importance, involving clinicians in the co-design of MLdementia models can ensure AI/ML tools meet clinical needs and foster greater acceptance and integration into practice.Last but not least, some clinicians are hesitant to accept AI/ML tools due to concerns about job displacement [122].However, it is essential to understand that AI/ML tools are designed to augment, not replace, the work of clinicians, similar to other diagnostic tests.Clinicians should be assured that their clinical judgment cannot be replaced by AI/ML and that the role of AI/ML in clinical practice should be clearly defined in relevant guidelines.

Ethics and regulatory considerations
The integration of AI/ML in healthcare brings forth numerous ethical and regulatory concerns that could potentially impede their implementation.Recently, the World Health Organization issued new guidance on the ethics and governance of AI technology applications in healthcare [123], emphasizing the need for AI/ML developers to prioritize ethical principles.To facilitate the potential implementation of AI/ML tools in dementia diagnosis and management, we also advocate for the development of local guidelines to fit the culture/ religious needs.On the regulatory front, compliance with healthcare regulations is indispensable.Regulatory bodies, such as FDA, the European Medicines Agency, and the Therapeutic Goods administration (Australia), should get prepared for processing more applications for AI/ML medical devices in the future.A clear approach must be established for post-deployment continuous monitoring and reporting, to maintain their safety and effectiveness in the clinic [122].More importantly, it is crucial that regulations should clearly define the responsibilities and accountabilities of AI/ML developers and healthcare providers for any errors generated by AI/ML tools.This includes specifying the extent of liability for developers in the event of AI/ML malfunction or incorrect predictions, as well as outlining the role of healthcare providers in interpretating AI/ML outputs before making clinical decisions.Regulations should also detail mechanisms for reporting and addressing errors, as well as protocols for updating and improving AI/ML tools from reported errors.An in-depth discussion on regulatory matters concerning ML/AI is outside the scope of this review.Regulatory bodies, clinicians, and public health experts are encouraged to work on regulatory matters to prepare our healthcare systems for the implementation of AI/ML tools.

Fig. 2
Fig. 2 General machine learning model workflows in clinical settings.AUC = area under the curve; MSE = mean squared error.This figure is created using Canva (www.canva.com)

Table 1
Major longitudinal datasets used in ML-dementia

Table 1 (
continued)This is not an exhaustive list of all datasets available for AD research globally.The datasets were selected based on the following criteria: 1) open-access observational datasets, 2) more than 1,000 participants, and 3) prominent use in ML-dementia models developed over the last 10 years.The list is ordered by the year in which the cohort study began Abbreviations: A4 Anti-Amyloid Treatment in Asymptomatic Alzheimer's study, ADNI Alzheimer's Disease Neuroimaging Initiative, AIBL The Australia Imaging, Biomarker and Lifestyle Study, ALFA Alzheimer and Families project, BLSA The Baltimore Longitudinal Study of Aging, BNA The French National Alzheimer Database, CLHLS Chinese Longitudinal Healthy Longevity Survey, CLSA The Canadian Longitudinal Study on Aging, EMIF-AD MBD European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, NACC The National Alzheimer's Coordinating Center, OASIS Open Access Series of Imaging Studies, ROSMAP Religious Orders Study and Rush Memory and Aging Project, TILDA The Irish Longitudinal Study on Ageing, WRAP Wisconsin Registry for Alzheimer's Prevention

Table 3
Examples of machine learning models

Table 4
[58] NIA-AA research framework[58]for biological definition of Alzheimer's disease A: amyloid-beta levels detected by PET or cerebrospinal fluid analysis T: tau pathology evidenced by tangles and PET or cerebrospinal fluid biomarkers N: neurodegeneration indicated by MRI atrophy,18F-Fluorodeoxyglucose-PET hypometabolism, or high cerebrospinal fluid tau

Table 6
CDR-SB and MMSE scores for cognitive health classificationCDR-SB Clinical Dementia Rating-Sum of Boxes, MMSE Mini-Mental State Examination

Table 7
Dementia ML models using non/less-invasive data as input predictors

Table 7
Abbreviations: A4Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease, ADNI Alzheimer's disease Neuroimaging Initiative, NACC-UDS National Alzheimer's coordinating center uniform data set, NIFD National institute of Fashion Designing, NINCDS-ADRDA National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association, ROSMAP Religious Orders Study and Rush memory and Ageing; SMG-SNU Seoul Metropolitan Government -Seoul National University, ACC accuracy, Aβ + amyloid-beta positive, Aβ-amyloid-beta negative, ACD all-cause dementia, ADem Alzheimer's dementia, AFT accelerated failure time model, ANN artificial neural network, APOE apolipoprotein E, AUC area under the receiver operating characteristic curve, CART category and regression tree, CPH cox proportional hazard regression model, CSF cerebrospinal fluid, CU cognitive unimpairment, CUs cognitive unimpairment stable (i.e., no progression to MCI or AD), Cup cognitive unimpairment progression (i.e., progression from CU to MCI/AD), DLB dementia with Lewy bodies, DT decision tree, eMCI early mild cognitive impairment, GB gradient boosting, KNN k-nearest neighbour, LASSO least absolute shrinkage and selection operator, LightGBM light gradient boosting machine, LMCI late mild cognitive impairment, LR linear regression, LSTM long short-term memory, MAE mean absolute error, MCI mild cognitive impairments, MCIs mild cognitive impairment stable, MCIp mild cognitive impairments progression to Alzheimer's dementia, MLP multilayer perceptron, MMSE Mini Mental State Examination, PET positron emission tomography, RF random forest, RNN recurrent neural networks, SMC significant memory concern, SVM support vector machine, VaD vascular dementia, XGBoosting eXtreme gradient boosting

Table 8
Challenges, solutions and future directions